Age-Dependent Estrogen-Independent Mechanism of Hyposomatotropism in Women

描述（由申请人提供）：临床内分泌学的一个主要未解决的问题是衰老如何损害合成代谢激素的产生，如生长激素和igf - 1。一个科学的僵局出现了，因为现有的研究被年龄和性腺激素之间的强烈相互依赖所混淆，性腺激素也维持生长激素的产生。区分这两个因素的作用对于制定合理的非甾体相对于甾体干预措施以避免与年龄相关的营养激素驱动丧失至关重要。考虑到生长激素输出减少与骨质减少、肌肉减少、健康受损、内脏肥胖、胰岛素抵抗以及心血管发病率和死亡率增加有关，这个主题很重要。作为解决这一基本问题的一种新方法，我们最近验证了一个短期系统性雌二醇（E2）钳位在健康绝经前和绝经后妇女中的调查模型，该模型清晰地分离了年龄层和雌激素可用性对生长激素分泌和相应的IGF-I产生的影响，并区分了23%的腹部内脏脂肪量（AVF）。这个框架将允许我们第一次解析介导绝经后和绝经前年龄和雌激素状态对生长激素可用性的单独和联合影响的基本机制。这篇论文提出，衰老和雌激素剥夺通过改变有限的相互联系的肽群来减少生长激素的分泌：(1)GH释放激素（GHRH）；（ii）释放gh。肽(GHRP /饥饿激素);（三）生长抑素。这三种信号在生理上是相互联系的，这意味着没有一种肽单独起作用，也没有一种肽可以单独有效地解释。通过将肽基信号配对传递，然后评估年龄和E2可用性（在可比较的AVF下）如何决定第三种（内源性）效应肽的作用，将对整体连通性进行实验剖析。这一新策略将允许在以下假设下对年龄和E2的不同影响进行无创量化：假设1：年龄降低，而E2增强内源性GHRH和内源性ghrelin对GH分泌的前馈驱动；相反，年龄会升高，E2会减弱内源性SS对生长激素分泌的抑制作用。假设二：年龄会减弱，E2会增强ghrelin的推测能力：(1)在脉动性GHRH刺激下增强生长激素分泌；（ii）增加间歇性SS抑制引起的反弹样GH分泌。假设三：年龄和E2可用性共同调节游离（蛋白未结合）IGF-I的浓度依赖性负反馈，从而控制平均每日生长激素分泌。方法包括对绝经后和绝经前妇女进行低水平和生理性E2钳夹；对AVF的混淆进行调整；以及应用一种通用的分析形式来重建生长激素分泌的整体控制。因此，期望是建立年龄层相对于雌激素剥夺对绝经后环境中促性腺功能减退的机制贡献。了解绝经后年龄（独立于E2消耗）对生长激素产生的中枢调节的基本机制，应该促进创新方法，在不需要雌激素补充的情况下，预防老年妇女生长激素/ igf - 1可用性的下降。绝经后妇女服用雌激素的风险有限，在某些患者群体中是禁忌的。因此，本研究旨在揭示控制主要营养激素GH和igf - 1产生的基本机制，这些激素维持骨骼和肌肉质量，减少腹部脂肪并提高生活质量。

DESCRIPTION (provided by applicant): A major unresolved question in clinical endocrinology is how aging impairs the production of anabolic hormones, such as GH and IGF-I. A scientific impasse arises because existing studies are confounded by the strong interdependence between age and gonadal sex steroids, which also maintain GH production. Distinguishing the roles of these two factors is central to framing rational nonsteroidal vis-a-vis steroidal interventions to obviate age-associated loss of trophic-hormone drive. The theme is important, given that diminished GH output is associated with osteopenia, sarcopenia, impaired well being, visceral adiposity, insulin resistance, and increased cardiovascular morbidity and mortality. As a novel approach to this fundamental problem, we recently validated an investigative model of a short-term systemic estradiol (E2) clamp in healthy premenopausal and postmenopausal women that vividly separates the impact of age stratum and estrogen availability on GH secretion and attendant IGF-I production, and discriminates a 23% contribution of abdominal visceral fat mass (AVF). This framework will allow us to parse for the first time the fundamental mechanisms that mediate separate and combined effects of post- and premenopausal age and estrogenic status on GH availability. The thesis advanced is that aging and estrogen deprivation reduce GH secretion by modifying a finite ensemble of interlinked peptides: (i) GH-releasing hormone (GHRH); (ii) GH-releasing . peptide (GHRP/ghrelin); and (iii) somatostatin. The fact that all 3 signals are physiologically interlinked means that no single peptide acts alone or may be validly interpreted in isolation. Ensemble connectivity will be dissected experimentally by delivering peptidyl signals in pairs and then assessing how age and E2 availability (at comparable AVF) determine actions of the third (endogenous) effector peptide. This new stratagem will permit noninvasive quantification of distinct effects of age and E2 under the following hypotheses: Hypothesis I: Age reduces whereas E2 enhances feedforward drive of GH secretion by endogenous GHRH and endogenous ghrelin; and conversely age elevates and E2 attenuates inhibition of GH secretion by endogenous SS. Hypothesis II: Age attenuates and E2 potentiates the putative capabilities of ghrelin to: (i) amplify GH secretion driven by pulsatile GHRH stimulation; and (ii) augment rebound-like GH secretion evoked by intermittent SS inhibition. Hypothesis III: Age and E2 availability jointly modulate concentration-dependent negative feedback by free (protein-unbound) IGF-I, thus controlling mean daily GH secretion. Methodologies will include a low and physiological E2 clamp in both post- and premenopausal women; adjustments for confounding by AVF; and application of a versatile analytical formalism to reconstruct ensemble control of GH secretion. The expectation thereby is to establish the mechanistic contributions of age stratum vis-a-vis estrogen deprivation to hyposomatotropism in the postmenopausal setting. Understanding the fundamental mechanisms by which postmenopausal age, independently of E2 depletion, impairs central regulation of GH production should foster innovative approaches to forestall the decline in GH/IGF-I availability in aging women without necessarily requiring estrogen repletion. Public Precis Estrogen administration in postmenopausal women carries a finite risk and is contraindicated in some patient groups. Therefore, this proposal seeks to unravel fundamental mechanisms that control the production of the major trophic hormones GH and IGF-I, which maintain bone and muscle mass, reduce abdominal fat and enhance quality of life.